Merck’s Zetia/atorvastatin combo pill unlikely to gain FDA nod until cardiovascular impact results available

This article is provided to FT.com readers by BioPharm Insight—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.biopharminsight.com

--------------------------------------------------------------------------------

Merck’s (NYSE:MRK) combination Zetia/atorvastatin cholesterol pill is unlikely to reach the market this year as intended, as regulators will likely first require data from a larger trial, known as IMPROVE-IT, experts told BioPharm Insight.

IMPROVE-IT is meant to evaluate the ability of Merck’s Vytorin, which contains Zetia, to lower the rate of cardiovascular (CV) events such as heart attack and nonfatal stroke. Merck’s marketing application for the Zetia/atorvastatin tablet to the US Food and Drug Administration was based on studies that tested the combination tablet’s impact on cholesterol levels.

In light of Merck’s recent failure in the HPS2-THRIVE CV outcomes trial of Tredaptive, experts indicated the FDA is apt to require IMPROVE-IT results for the Zetia/atorvastatin combination prior to approval.

Tredaptive is a “good” cholesterol, or HDL, raising drug, while the new combination lowers “bad” LDL cholesterol. The pill couples Merck’s Zetia (ezetimibe) and a generic version of Pfizer’s (NYSE:PFE) statin blockbuster Lipitor.

Lipitor sales peaked in 2006 at USD 12.87bn. In 2011, the drug made USD 9.58bn. Zetia US sales in 2011 were USD 2.43bn, with peak sales expected at USD 2.63bn in 2016, according to BioPharm Insight data.

Merck announced in March 2012 the previously projected 2013 study completion date for IMPROVE-IT may change in light of the rate at which CV events are being reported, a company spokesperson said. Based on the current rate at which events are being reported, the company now anticipates the targeted 5,250 events for study completion will be reached in 2014, he said.

On 2 January 2013, Merck reported the FDA acknowledged the resubmission of a New Drug Application (NDA) to market the Zetia/atorvastatin combination therapy, known as MK-0653C. The updated NDA was deemed complete for review after Merck submitted additional data in response to the FDA’s Complete Response Letter (CRL) issued last March, which requested data from three studies. IMPROVE-IT was not mentioned in Merck’s statement regarding last year’s CRL.

Merck expects the FDA’s review to be completed in 1H13, according to a company press release. “We are not going to speculate on what the FDA may request in their review of the NDA,” a company spokesperson said.

FDA approval for combo pill hinges on IMPROVE-IT

The 18,000-patient IMPROVE-IT trial is comparing the effect of Vytorin, a combination of the company’s statin drug Zocor (simvastatin), now generically available, and Zetia, to Zocor alone. The FDA approved Zocor in 1991, Lipitor in 1996, Zetia in 2002 and Vytorin in 2004.

Considering data on Lipitor’s effects on CV events is available, IMPROVE-IT results would be sufficient, rather than results from an all together new trial of the Zetia/atorvastatin combo pill’s effects on CV events, according to Kevin Maki, president and chief science officer, Biofortis-Provident Clinical Research, Illinois. IMPROVE-IT would provide information regarding Zetia’s effects on CV events, he explained.

While it is hard to predict the FDA, the Zetia/atorvastatin combo may be delayed until full IMPROVE-IT results are in, said Dr Sekar Kathiresan, director, Preventive Cardiology, Massachusetts General Hospital. It would not be prudent to approve the combination drug without knowing the IMPROVE-IT results, added Dr Steven Nissen, chairman, Cardiovascular Medicine department, Cleveland Clinic. The FDA may await the IMPROVE-IT trial before reconsidering the Zetia/atorvastatin combination, agreed Dr Robert Eckel, professor of medicine, director of endocrinology, metabolism and diabetes, University of Colorado Anschutz Medical Campus.

This sentiment was echoed by Jonathan Cohen, C. Vincent Prothro Distinguished Chair in Human Nutrition Research, University of Texas Southwestern Medical Center and Dr Philip Barter, president, International Atherosclerosis Society, Sydney, Australia.

After the HPS2-THRIVE failure, the FDA is apt to be careful in taking any new steps, said Dr Joep Perk, Chair of the Fifth Joint European Societies’ Taskforce on CV Disease Prevention, Linnaeus University, Sweden. HPS2-THRIVE failed as Tredaptive - a combination of the cholesterol drug niacin and laropiprant, which counters niacin’s facial flushing effects - was no better than placebo at reducing risk of heart attack, coronary death, stroke or the need for arterial bypass procedures.

IMPROVE-IT has low chances for success, experts previously told BioPharm Insight. They indicated the acute coronary syndrome patient population being assessed does not bode well for a successful trial, as lowering LDL levels in these individuals may not have a big effect on CV events.

Maki reiterated he is not confident IMPROVE-IT will be favorable, but expects that the Zetia/atorvastatin combination would sell very well should IMPROVE-IT show good results. Perk agreed he is doubtful IMPROVE-IT will be successful, as Zetia’s benefit on top of a statin is likely to be marginal.

Merck’s market cap is USD 128.6bn.

--------------------------------------------------------------------------------

For more information or to inquire about a trial please email sales@biopharminsight.com or call Americas: +1 212-500-1384 or Europe: 44 (0)20 7059 6202